Paroxetine, (−)-trans-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl) piperidine; (3S, 4R)-3-[5-(1,3-dioxaindanyl)oxymethyl]-4-(p-fluorophenyl)piperidine, is a 5-hydroxytryptamine (5-HT, serotonin) re-uptake inhibitor having the formula:

Paroxetine, disclosed in U.S. Pat. No. 4,007,196 (incorporated herein by reference), is prescribed for the treatment of psychiatric problems including depression, Parkinson's disease, anxiety disorders, obsessive-compulsive disorders, panic disorder and post-traumatic stress disorder. Other syndromes such as pre-menstrual syndrome (PMS) and male sexual dysfunction can also be treated with paroxetine.
Paroxetine is marketed as Paxil® in the U.S. and as Seroxat® in other countries by GlaxoSmithKline. Paxil® is prescribed as oral dosage tablets containing 10 mg, 20 mg, 30 mg and 40 mg of the base equivalent of paroxetine hydrochloride. Paxil® tablets include dibasic calcium phosphate dihydrate, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycols, polysorbate 80, sodium starch glycolate, titanium dioxide and one or more of the following: D&C Red No. 30, D&C Yellow No. 10, FD&C Blue No. 2, FD&C Yellow No. 6.
Paxil® is also available as an oral suspension with a dosage of 10 mg of the base equivalent of paroxetine hydrochloride in a 5 mL suspension containing polacrilin potassium, microcrystalline cellulose, propylene glycol, glycerin, sorbitol, methyl paraben, propyl paraben, sodium citrate dihydrate, citric acid anhydrous, sodium saccharin, flavorings, FD&C Yellow No. 6 and simethicone emulsion, USP.
Commercial paroxetine tablets, such as Paxil® and Seroxat® contain paroxetine as paroxetine hydrochloride (HCl) hemihydrate. Although Paxil® and Seroxat® contain HPMC, it is believed that HPMC is a component of the coating in these tablets, which are probably manufactured by a direct compression method. It is believed that these tablets do not contain a binder.
Many problems are associated with paroxetine hydrochloride tablets. See e.g. WO 00/32593, incorporated herein by reference. One such problem is the susceptibility to changes in mechanical properties, particularly hardness. Paroxetine hydrochloride tablets are particularly susceptible to becoming soft during storage, especially under accelerated aging conditions. In tests performed under accelerated aging conditions, tablets of Seroxat® and those containing HPMC as a binder and microcrystalline cellulose as a filler lost a substantial amount of their hardness, more than about 40%. Thus, there is a continuing need to improve the preparation and formulations of paroxetine hydrochloride oral dosage forms, particularly tablets.